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Press Release October 9, 1995
The Nobel Assembly at the Karolinska Institute has today decided to
award the Nobel Prize in Physiology or Medicine for 1995 jointly to
Edward B. Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus
for their discoveries concerning
"the genetic control of early embryonic development"
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Summary
The 1995 laureates in physiology or medicine are developmental
biologists who have discovered important genetic mechanisms which
control early embryonic development. They have used the fruit fly,
Drosophila melanogaster , as their experimental system. This organism
is classical in genetics. The principles found in the fruit fly, apply
also to higher organisms including man.
Using Drosophila Nüsslein-Volhard and Wieschaus were able to identify
and classify a small number of genes that are of key importance in
determining the body plan and the formation of body segments. Lewis
investigated how genes could control the further development of
individual body segments into specialized organs. He found that the
genes were arranged in the same order on the chromosomes as the body
segments they controlled. The first genes in a complex of
developmental genes controlled the head region, genes in the middle
controlled abdominal segments while the last genes controlled the
posterior ("tail") region. Together these three scientists have
achieved a breakthrough that will help explain congenital
malformations in man.
What controls the development of the fertilized egg?
The fertilized egg is spherical. It divides rapidly to form 2, 4 , 8
cells and so on. Up until the 16-cell stage the early embryo is
symmetrical and all cells are equal. Beyond this point, cells begin to
specialize and the embryo becomes asymmetrical. Within a week it
becomes clear what will form the head and tail regions and what will
become the ventral and dorsal sides of the embryo. Somewhat later in
development the body of the embryo forms segments and the position of
the vertebral column is fixed. The individual segments undergo
different development, depending on their position along the
"head-tail" axis. Which genes control these events? How many are they?
Do they cooperate or do they exert their controlling influence
independently of each other?
This year' s laureates have answered several of these questions by
identifying a series of important genes and how they function to
control the formation of the body axis and body segments. They have
also discovered genes that determine which organs that will form in
individual segments. Although the fruit fly was used as an
experimental system, the principles apply also to higher animals and
man. Furthermore, genes analogous to those in the fruit fly have been
found in man. An important conclusion is that basic genetic mechanisms
controlling early development of multicellular organisms have been
conserved during evolution for millions of years.
Brave decision by two young scientists
Christiane Nüsslein-Volhard and Eric Wieschaus both finished their
basic scientific training at the end of the seventies. They were
offered their first independent research positions at the European
Molecular Biology Laboratory (EMBL) in Heidelberg. They knew each
other before they arrived in Heidelberg because of their common
interest: they both wanted to find out how the newly fertilized
Drosophila egg developed into a segmented embryo. The reason they
chose the fruit fly is that embryonic development is very fast. Within
9 days from fertilization the egg develops into an embryo, then a
larvae and then into a complete fly.
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Fig. 1. Regions of activity in the embryo for the genes belonging to
the gap, pair-rule, and segment-polarity groups. The gap genes start
to act in the very early embryo (A) to specify an initial segmentation
(B). The pair-rule genes specify the 14 final segments (C) of the
embryo under the influence of the gap genes. These segments later
acquire a head-to-tail polarity due to the segment polarity genes.
They decided to join forces to identify the genes which control the
early phase of this process. It was a brave decision by two young
scientists at the beginning of their scientific careers. Nobody before
had done anything similar and the chances of success were very
uncertain. For one, the number of genes involved might be very great.
But they got started. Their experimental strategy was unique and well
planned. They treated flies with mutagenic substances so as to damage
(mutate) approximately half of the Drosophila genes at random
(saturation mutagenesis). They then studied genes which, if mutated
would cause disturbances in the formation of a body axis or in the
segmentation pattern. Using a microscope where two persons could
simultaneously examine the same embryo they analyzed and classified a
large number of malformations caused by mutations in genes controlling
early embryonic development. For more than a year the two scientists
sat opposite each other examining Drosophila embryos resulting from
genetic crosses of mutant Drosophila strains. They were able to
identify 15 different genes which, if mutated, would cause defects in
segmentation. The genes could be classified with respect to the order
in which they were important during development and how mutations
affected segmentation. Gap genes (Fig 1) control the body plan along
the head-tail axis. Loss of gap gene function results in a reduced
number of body segments. Pair rule genes affect every second body
segment: loss of a gene known as "even-skipped" results in an embryo
consisting only of odd numbered segments. A third class of genes
called segment polarity genes affect the head-to-tail polarity of
individual segments.
The results of Nüsslein-Volhard and Wieschaus were first published in
the English scientific journal Nature during the fall of 1980. They
received a lot of attention among developmental biologists and for
several reasons. The strategy used by the two young scientists was
novel. It established that genes controlling development could be
systematically identified. The number of genes involved was limited
and they could be classified into specific functional groups. This
encouraged a number of other scientists to look for developmental
genes in other species. In a fairly short time it was possible to show
that similar or identical genes existed also in higher organisms and
in man. It has also been demonstrated that they perform similar
functions during development.
The fly with the extra pair of wings
Already at the beginning of this century geneticists had noted
occasional malformations in Drosophila. In one type of mutation the
organ that controls balance (the halteres), was transformed into an
extra pair of wings (Fig. 2). In this type of bizarre disturbance of
the body plan, cells in one region behave as though they were located
in another. The Greek word homeosis was used to describe this type of
malformations and the mutations were referred to as homeotic
mutations.
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Fig. 2. Comparison of a normal and a four-winged fruit fly. The third
thoractic segment has developed as a duplicate of the second due to a
defectic homeotic gene. In the normal fly only the second segment
develops wings.
The fly with the extra pair of wings interested Edward B. Lewis at the
California Institute of Technology in Los Angeles. He had, since the
beginning of the forties, been trying to analyze the genetic basis for
homeotic transformations. Lewis found that the extra pair of wings was
due to a duplication of an entire body segment. The mutated genes
responsible for this phenomenon were found to be members of a gene
family (bithorax-complex) that controls segmentation along the
anterior-posterior body axis (Fig. 3). Genes at the beginning of the
complex controlled anterior body segments while genes further down the
genetic map controlled more posterior body segments (the colinearity
principle). Furthermore, he found that the regions controlled by the
individual genes overlapped, and that several genes interacted in a
complex manner to specify the development of individual body segments.
The fly with the four wings was due to inactivity of the first gene of
the bithorax complex in a segment that normally would have produced
the halteres, the balancing organ of the fly (Fig 3). This caused
other homeotic genes to respecify this particular segment into one
that forms wings.
Edward Lewis worked on these problems for decades and was far ahead of
his time. In 1978 he summarized his results in a review article and
formulated theories about how homeotic genes interact, how the gene
order corresponded to the segment order along the body axis, and how
the individual genes were expressed. His pioneering work on homeotic
genes induced other scientists to examine families of analogous genes
in higher organisms. In mammalians, the gene clusters first found in
Drosophila have been duplicated into four complexes known as the HOX
genes. Human genes in these complexes are sufficiently similar to
their Drosophila analogues they can restore some of the normal
functions of mutant Drosophila genes.
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Fig. 3. The principle of colinearity in Drosophila (A-C) and mouse
(Mus musculus, D-F) embryos. The horizontal bars indicate in which
areas the homeotic genes 1-9 are active along the body axis. Gene 1 is
active in the head region (left in A and F, respectively); gene 9 is
active in the tail region (right). Gene 7 of the bithorax complex was
inactive in the fly with four wings. The bar showing its normal range
of activity is indicated with an asterisk.
The individual genes within the four HOX gene families in vertebrates
occur in the same order as they do in Drosophila , and they exert
their influence along the body axis (Fig 3 D-F) in agreement with the
colinearity principle first discovered by Lewis in Drosophila. More
recent research has suggested that the segments where shoulders and
the pelvis form is determined by homeotic genes.
Congenital malformations in man
Most of the genes studied by Nüsslein-Volhard, Wieschaus and Lewis
have important functions during the early development of the human
embryo. The functions include the formation of the body axis, i.e. the
polarity of the embryo, the segmentation of the body, and the
specialization of individual segments into different organs. It is
likely that mutations in such important genes are responsible for some
of the early, spontaneous abortions that occur in man, and for some of
the about 40% of the congenital malformations that develop due to
unknown reasons. Environmental factors such as very high doses of
vitamin A during early pregnancy are also known to disturb the
regulation of HOX-genes, thus inducing severe congenital
malformations.
In some cases have mutations been found in human genes related to
those described here for Drosophila. A human gene related to the
Drosophila gene paired will cause a condition known as Waardenburg"'"s
syndrome. It is a rare disease which involves deafness, defects in the
facial skeleton and altered pigmentation of the iris. Another
developmental gene mutation causes a complete loss of the iris, a
condition known as aniridia.
Literature
Lewis, E.B. (1978) A Gene Complex Controlling Segmentation in
Drosophila.
Nature 276, 565-570
Nüsslein-Volhard, C., Wieschaus, E. (1980). Mutations Affecting
Segment Number and Polarity in Drosophila. Nature 287, 795-801
McGinnis, W., Kuziora, M. (1994). The Molecular Architects of Body
Design.
Scientific American 270, 36-42
Lawrence, P. The Making of a Fly. Blackwell Scientific Publications.
Oxford 1992.
The Molecular Biology of the Cell. Eds Alberts, B. et al, 3rd edition
pp 1077-1107.
Garland Publishing, New York 1994.